The ALDH2 gene is of interest for alcoholism research because of the protection against alcoholism afforded by deficiency of this enzyme. The Principal Investigator is interested in the control of transcription of the ALDH2 gene, and hypothesizes that mutations in the control regions or environmental factors that reduce expression of the gene may also provide protection against the development of alcoholism. During the last period of support, the effect of the ALDH2*2 mutation on ALDH2 enzyme activity was characterized, and a number of transcription factors were identified that can bind the ALDH2 promoter and affect the expression of reporter genes derived from the ALDH2 promoter. These studies will be extended by: 1) more completely defining the role of an A/G polymorphism in the ALDH2 promoter; 2) determining the ability of additional selected nuclear receptors to bind the ALDH2 promoter; 3) further defining the control of ALDH2 expression by HNF-4 and retinoid receptors by analyzing effects of ligand levels and phosphorylation of the receptors; 4) better defining the factors binding an upstream E box and examining their ability to affect expression of the gene; 5) testing the function of these promoter sites by transfection studies using primary hepatocyte cultures; and 6) determining the effect of ligands for retinoid receptors, HNF-4, and peroxisome proliferator activated receptors on expression of ALDH2 protein in rats. The effect of chronic ethanol consumption and of genetic deficiency of PPARalpha on ALDH2 expression will also be tested. These studies should further our understanding of the tissue-specific control of ALDH2 and the potential that dietary factors have on its expression.